tbuckley/cabot-search huggingface dataset:
HGG-42. Evolutionary selection of key oncogenic alterations in patient-derived models of paediatric diffuse high grade glioma (PDHGG) subtypes<i>in vitro</i> and<i>in vivo</i>
Authors: Alan Mackay, Sara Temelso, Diana Carvalho, Ketty Kessler, Jessica Boult, Elisa Izquierdo, Rita Pereira, Elisabet Fernandez Potente, Anna Burford, Valeria Molinari, Lynn Bjerke, Yura Grabovska, Rebecca Rogers, Shauna Crampsie, Molina Das, Simon Robinson, Matthew Clarke, Chris Jones
Journal: Neuro-Oncology (2022)

Abstract PDHGG are a diverse group of childhood brain tumours comprising multiple subgroups carrying distinct molecular drivers. Patient-derived models accurately recapitulating this underlying biology are critical for mechanistic/preclinical studies aimed at improving patient outcome, however their behaviour over time in the environments in which they are propagated, and how this relates to the human disease, is largely unknown. To explore this, we collected 94 models of PDHGG established as 2D/3D stem cell cultures in vitro, and generated patient-derived xenografts (PDX) in 33/62 specimens implanted orthotopically in vivo. We carried out exome/targeted sequencing, methylation profiling and RNAseq to profile cells through their first 25 passages in culture, and sequential implantation from p0-p2 in mice. In 15/83 cultures, we observed enrichment of gene expression signatures of non-malignant cells over the first 5 passages, with concurrent depletion of somatic mutations/CNAs, excluding them from further study. Validated models retained tumour-matched genotypes, CNAs and driver alterations including H3.3G34R, H3.3/H3.1K27M, BRAF and ACVR1 over time, however subclonal alterations underwent selection in culture which profoundly altered their response to targeted drug treatment. In 6/7 PDGFRA-mutant models, activating mutations were selected against between p5-20 in 2D and/or 3D, whilst MAPK pathway mutations in NF1/PIK3R1 similarly diverged over 15 passages under different growth conditions, resulting in isogenic models with differential signalling, in vivo tumorigenicity, and in vitro sensitivity to multiple MEK inhibitors. In PDXs, serial xenografting reduced the time to tumour formation by up to half, with a concomitant shift in clonal architecture. Multi-region sequencing of diffusely-infiltrating tumours showed selection for alterations such as PIK3CA/NF1 at distant sites, with evidence for convergent evolution of subclonal mutations, as in human tumours. Understanding the evolutionary dynamics of targetable/predictive alterations in PDHGG model systems is key to developing new and effective therapeutic interventions in this highly heterogenous disease.
Re: Christian Radmayr’s Words of Wisdom re: Fertility Potential Is Compromised in 20% to 25% of Boys with Nonsyndromic Cryptorchidism Despite Orchidopexy Within the First Year of Life. Eur Urol. 2022;82:143
Authors: Faruk Hadziselimovic, Gilvydas Verkauskas, Guy Bogaert
Journal: European Urology (2022)
RARE-13. Clinical management and functional and survival outcomes in pediatric craniopharyngioma, a patient and family perspective
Authors: Emily Marshall, Sylvia Cheng, Julia Crowley, Shana McCormack, Brian Rood, Todd Hankinson, Michael DeCuypere, Sandy Lam, Stewart Goldman, Svenja Boekhoff, Hermann L Muller, Ryan Velasco, Phillip B Storm, Adam Resnick, Michael Prados, Sabine Mueller, Cassie Kline, Fatema Malbari
Journal: Neuro-Oncology (2022)

Abstract Craniopharyngiomas are rare, histologically benign, sellar/parasellar tumors with significant tumor and therapy related morbidity and impairment in quality of life (QOL). We report survey results from patients/families affected by childhood-onset craniopharyngioma to identify opportunities for improvement in management. An anonymous REDCap survey was distributed via social media and clinic visits to patients/families of craniopharyngioma survivors. Survey questions investigated perspectives on clinical management and functional and survival outcomes at initial diagnosis and recurrence. A total of 159 patients/families completed the survey, 40% (n=64) reported craniopharyngioma recurrence. For primary craniopharyngioma, maximal safe resection was the most frequent treatment reported (n=84), followed by partial resection (n=40), radiation (n=8), biopsy (n=5), and chemotherapy (n=3). Most patients (n=120) decided on a treatment plan within one week, 63 (40%) decided in one day. For recurrent craniopharyngioma, maximal safe resection and radiation were the most frequent interventions (n=33 each), followed by partial resection (n=13), chemotherapy (n=4) and biopsy (n=2). Multiple treatment options and/or participation in a clinical trial were offered to similar numbers of patients across primary and recurrent diagnoses (~21% for each). Most recurrent craniopharyngioma patients decided on management within one week (n=43). Long term effects related to tumor and treatment were identified as the primary concern in all respondents. The most common deficits for all patients were neuro-endocrine followed by vision and neurocognition problems. Neuro-endocrine complications were self-reported as the biggest impact on QOL. Families reported that they would prefer treatment options with the potential for improved QOL, even if these options also carried an increased risk of recurrence. Craniopharyngioma continues to be predominantly treated with surgery and radiation initially and with recurrence. Survivors have multiple comorbidities, with an interest in targeted therapies that preserve QOL. Novel therapies to prevent co-morbidities and provide long term benefits are necessary and upcoming.
Towards a more systematic evaluation of cancer endpoints: A method for synthesis and analysis of NSCLC regulatory filings and clinical evidence.
Authors: Jennifer M. Hinkel
Journal: Journal of Clinical Oncology (2022)

e18681 Background: Ongoing debate surrounds the use of surrogate and proxy endpoints in oncology such as Progression Free Survival (PFS) and Overall Response Rate (ORR); the oncology community has debated the utility, meaningfulness, validity, and evidentiary definitions of such outcomes. Literature across disease states points to potential inconsistencies in the reporting of, and definition of, clinical trial endpoints more broadly. No data source currently exists to robustly analyze how endpoints are defined, deployed, and applied across a number of trials within a particular tumor type, let alone across oncologic diseases more broadly. This study presents a systematic method to build such a dataset using regulatory filings and clinical evidence publications. Methods: This study developed a five-step method to synthesize and analyze data in a systematic manner. Given the number of new therapeutic approvals in NSCLC, it was selected as a disease area of focus to test the method. For each step of the method, data was extracted and recorded in a Google Sheets database. Step 1 identified therapy FDA approvals from 2016-2020 via systematic search of the FDA website. Step 2 searched the Drugs@FDA database to identify approval packages. Step 3 synthesized the clinical evidence supporting approvals through systematic analysis of FDA Review Documents. Step 4 identified the published protocol for each study from Step 3 using ClinicalTrials.gov. Step 5 identified publications reporting results from Step 4 using the National Clinical Trial identifier numbers and keywords. Results: A systematic search and synthesis of FDA and clinical trial documentation in this manner yielded a dataset of six first approvals for NSCLC and 27 line extensions for NSCLC indications between 2016 and 2020. Conclusions: Informed debate around the use of proxy and surrogate endpoints is difficult to achieve without an evidentiary basis for the discussion. At present, no data source exists for researchers to answer questions such as: “How frequently was PFS used as the primary endpoint in registrational trials for lung cancer over the past ten years?” By developing and deploying a systematic method as described above, researchers can build such a dataset, and then apply the same method across additional disease states and tumor types to understand a more comprehensive picture of how endpoints are defined, measured, and applied in clinical trials. Not only can such a dataset enable research that informs clinical trial design, but it can also enable research and policy development regarding endpoint fidelity, utility, and meaningfulness.
LGG-45. Genetic dependencies in<i>MYB/MYBL1</i>-driven pediatric low-grade glioma models
Authors: Alexandra-Larisa Condurat, Jill Jones, Elizabeth Gonzalez, Jeyna Doshi, Kevin Zhou, Jessica W Tsai, Prasidda Khadka, Graham B J Buchan, Cecile Rouleau, Kristine Pelton, Tanaz Abid, Amy Goodale, Nicole Persky, Rameen Beroukhim, Keith Ligon, David Root, Federica Piccioni, Pratiti Bandopadhayay
Journal: Neuro-Oncology (2022)

Abstract AIM: Pediatric low-grade gliomas (pLGGs) are a heterogenous group of tumors, diverse in their localization, histology, mutational landscape, clinical behavior, and treatment response. Genomic alterations impacting the MYB family of transcription factors were identified in two distinct pLGG subtypes: Angiocentric Gliomas (AG) and Diffuse Astrocytomas (DA). The molecular profiles and therapeutic vulnerabilities associated with these genomic alterations remain unexplored. In this study we highlight the use of genome-wide CRISPR/Cas9 knock-out screens for an unbiased identification of translatable therapeutic targets. METHODOLOGY: Given the lack of patient-derived pLGG cell lines, we engineered in vitro pLGG mouse and human neural stem cell (NSC) models to harbor pLGG-relevant genomic alterations. We performed single cell RNA sequencing to investigate the transcriptional profiles driven by these mutations and to dissect the central regulatory networks enabling tumorigenesis. Specific genetic dependencies associated with MYB/MYBL1 mutations were screened using the Brie genome-wide mouse CRISPR lentiviral knock-out pooled library, consisting of 78,637 single guide RNAs (sgRNAs) targeting 19,674 mouse genes. RESULTS: We have successfully generated in vitro NSC-based pLGG models crucial to deepening our knowledge on pLGG biology and the identification of translatable therapeutic targets. Genome-scale CRISPR/Cas9 knock-out screens in isogenic NSCs models, expressing distinct MYB/MYBL1 alterations or a control transgene, revealed several differential genetic dependencies. Among the top identified dependencies are regulators of cell-stress response, cell-cycle progression, and modulators of the ubiquitin-proteasome degradation pathway. CONCLUSION: Genome-wide CRISPR knock-out screens are a powerful tool for the unbiased identification of mutation-specific genetic dependencies that can be explored as candidates for precision medicine approaches.
Sources of Variation in the Carbon Footprint of Hemodialysis Treatment
Authors: Ashwini R. Sehgal, Jonathan E. Slutzman, Anne M. Huml
Journal: Journal of the American Society of Nephrology (2022)

Greenhouse gas emissions from hemodialysis treatment in the United States have not been quantified. In addition, no previous studies have examined how much emissions vary across facilities, treatments, and emission contributors.To estimate the magnitude and sources of variation in the carbon footprint of hemodialysis treatment, we estimated life-cycle greenhouse gas emissions in carbon dioxide equivalents (CO2-eq) associated with 209,481 hemodialysis treatments in 2020 at 15 Ohio hemodialysis facilities belonging to the same organization. We considered emissions from electricity, natural gas, water, and supply use; patient and staff travel distance; and biohazard and landfill waste.Annual emissions per facility averaged 769,374 kg CO2-eq (95% CI, 709,388 to 848,180 kg CO2-eq). The three largest contributors to total emissions were patient and staff transportation (28.3%), electricity (27.4%), and natural gas (15.2%). Emissions per treatment were 58.9 kg CO2-eq, with a three-fold variation across facilities. The contributors with the largest variation in emissions per treatment were transportation, natural gas, and water (coefficients of variation, 62.5%, 42.4%, and 37.7%, respectively). The annual emissions per hemodialysis facility are equivalent to emissions from the annual energy use in 93 homes; emissions per treatment are equivalent to driving an average automobile for 238 km (149 miles).Similar medical treatments provided in a single geographic region by facilities that are part of the same organization may be expected to have small variations in the determinants of greenhouse gas emissions. However, we found substantial variation in carbon footprints across facilities, treatments, and emission contributors. Understanding the magnitude and variation in greenhouse gas emissions may help identify measures to reduce the environmental effect of hemodialysis treatment.
A multiphase continuing education and quality improvement initiative to tailor treatment plans for patients with follicular lymphoma.
Authors: Joseph Kim, Timothy S. Fenske, Linda Gracie-King, Marc David Viens, Victor Ocana, Abhinav Binod Chandra, David Penberthy, Tori McCurdy
Journal: Journal of Clinical Oncology (2022)

e18651 Background: Data support the need for increasing shared decision-making (SDM) conversations to align treatment decisions with patient values and preferences (Kehl KL et al. JAMA Oncol. 2015). Combining certified interprofessional continuing education and quality improvement (QI) methods may accelerate how cancer clinicians translate evidence into real-world clinical practice when diagnosing and treating patients with follicular lymphoma (FL). This initiative was supported by educational grants from Genentech, a member of the Roche Group and Bristol Myers Squibb and managed by AXIS Medical Education and Q Synthesis. Methods: The project collaborators invited three community hospital-based cancer centers to participate in this 18-month longitudinal, multiphase CME/CE and QI initiative. Each cancer center performed a baseline assessment by reviewing how their clinicians diagnosed and treated patients with FL. This process involved chart reviews, focus group discussions, and online surveys. Each cancer center developed problem statements, aim statements, and implemented improvement projects around prognostic scoring, the use of molecular diagnostics, SDM, and treatment planning. Clinicians also participated in two live virtual continuing education interventions, co-moderated by an academic clinician with a focus in lymphoma (T.F.), as well as the medical director of the activity (J.K.) and received reinforcement messages following those activities. Results: Members of the multidisciplinary cancer care team from three cancer centers in AZ, TN, and VA participated in this initiative. Across all three cancer centers, the following educational outcomes were observed: 61% increase in knowledge about the concept of POD24 (early disease progression within 24 months of initiating therapy); 50% increase in knowledge and practice skills regarding tailored treatment planning based on patient risk factors and prognostic scores; 33% increase in knowledge around the benefits of incorporating SDM when developing treatment plans, and an 18% increase in knowledge about risk-based treatment plans. The QI projects resulted in a 56% improvement in prognostic scoring (incorporating tumor grade and stage), a 25% increase in documenting tumor burden, and a 22% increase in the use of molecular diagnostics. Conclusions: This multiphase education and QI program enabled cancer clinicians to improve monitoring patients for POD24 and risk assessment, incorporate molecular testing, engage in SDM conversations with patients, and formulate tailored treatment plans for patients with FL.
IMG-06. Comparing between MR spectroscopy done at 1.5T and 3T
Authors: Phua Hwee Tang, Sameema Nisa
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: In hospitals with heavily utilised MRI scanners, it may not be possible to schedule the patient on 1 particular scanner for all scans and thus this project was carried out to determine if there is any significant difference in the spectroscopy profile between 1.5 T and 3T MRI scanners late year 2021. AIM: To describe the MR spectroscopy profile of normal brain tissue performed on 1.5T and 3T MRI scanners in KK Women’s and Children’s Hospital. METHODS: Three healthy adult volunteers with normal body mass index underwent MRI brain scans after informed consent in this Institute Review Board approved study. MRI brain scans were performed on 1.5T General Electric MRI scanner and 3T Siemens Skyra MRI scanner 1 week apart. NAA/Cr, Cho/Cr and Cho/ NAA values were obtained from the right and left cerebral hemispheres. RESULTS: Average NAA/Cr in the right cerebral hemisphere is 2.06+/-0.10 at 1.5T. Average NAA/Cr in the left cerebral hemisphere is 2.01+/-0.23 at 1.5T. Average NAA/Cr in the right cerebral hemisphere is 1.56+/-0.09 at 3T. Average NAA/Cr in the left cerebral hemisphere is 1.81+/-0.29 at 3T. Average Cho/Cr in the right cerebral hemisphere 1.06+/-0.14 at 1.5T. Average Cho/Cr in the left cerebral hemisphere is 1.11+/-0.22 at 1.5T. Average Cho/Cr in the right cerebral hemisphere is 0.90+/-0.05 at 3T. Average Cho/Cr in the left cerebral hemisphere is 0.95+/-0.27 at 3T. Average Cho/NAA in the right cerebral hemisphere is 0.51+/-0.06 at 1.5T. Average Cho/NAA in the left cerebral hemisphere is 0.58+/-0.00 at 1.5T. Average Cho/NAA in the right cerebral hemisphere is 0.55+/-0.05 at 3T. Average Cho/NAA in the left cerebral hemisphere is 0.52+/-0.07 at 3T. CONCLUSION: MR spectroscopy values obtained from 1.5T and 3T MRI scanners show no significant difference(P&amp;gt;0.05).
ATRT-23. SIRT2 cooperates with SMARCB1 to induce a differentiation block in ATRT
Authors: Irina Alimova, Dong Wang, Angela Pierce, Senthilnath Lakshmanachetty, Eric Prince, Etienne Danis, Natalie Serkova, Krishna Madhavan, Ilango Balakrishnan, Min Yang, Henning Lin, Nicholas Foreman, Sujatha Venkataraman, Rajeev Vibhakar
Journal: Neuro-Oncology (2022)

Abstract Atypical Teratoid Rhabdoid Tumor is a highly aggressive pediatric brain tumor with poor prognosis driven by loss of the chromatin remodeling factor SMARCB1 that is responsible for determining cellular pluripotency and lineage commitment. The mechanisms by which SMARCB1 deletion results in tumorigenesis remain unclear. We investigated the effect of SIRT2 inhibition in ATRT which was identified as a primary dependency in ATRT. SIRT2 inhibition with shRNA or Thiomyristoyl (TM) decreased ATRT cell growth, inhibited clonogenic potential and leaded to the cell cycle arrest. SIRT2 inhibition effectively suppresses pluripotency-associated genomic programs, significantly changed stem cell frequency, decreased tumor-sphere formation of ATRT cells and attenuated tumor cell self-renewal. In vivo SIRT2 inhibition decreased oncogenic markers and increased accumulation neuronal differentiation markers. Furthermore, SIRT2 induced apoptosis, decreased tumor growth and prolonged survival in orthotopic xenograft models. Single-cell RNA transcriptome analysis of xenoftaft tumors reveals elimination of tumor cells expressing stem cell genes and expansion of tumor cells expressing differentiated genes following TM treatment in ATRT. We demonstrated that SIRT2 inhibition is a molecular vulnerability in SMARCB1-deleted ATRT.
The After-Dinner Dip
Authors: Gertrud L.G. Haverkamp, Richard G. Ijzerman, Jos Kooter, Yvonne H.M. Krul-Poel
Journal: New England Journal of Medicine (2022)

An 85-year-old woman was brought to the emergency department by emergency medical services after losing consciousness. The loss of consciousness occurred approximately 45 minutes after the patient finished eating dinner and was preceded by a sudden onset of sweating, palpitations, and a cold feeling. She had had similar but milder symptoms three times in the 2 weeks before presentation.
Mice deficient in endothelial cell-selective adhesion molecule develop left ventricle diastolic dysfunction
Authors: V Buncha, KA Fopiano, Y Tian, L Lang, Z Bagi
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): American Heart Association Background Dysfunction of vascular endothelium plays a key role in the development of left ventricular diastolic dysfunction (LVDD) in patients with heart failure with preserved left ventricular ejection fraction (HFpEF). Recently, Endothelial Cell-Selective Adhesion Molecule (ESAM) was proposed as a novel biomarker in HFpEF. Hypothesis. ESAM plays a mechanistic role in the development of both microvascular dysfunction and LVDD. Methods Animals: The study was performed utilizing ESAM knockout and wild type (WT) mice. Echocardiography: Left ventricular (LV) systolic and diastolic function and LV wall thickness were assessed by small animal ultrasound imaging (Vevo3100). Blood pressure measurement: Performed with tail-cuff plethysmography method. Vascular reactivity: Pulmonary arteries (2nd and 3rd order) were isolated from ESAM KO and WT mice, vascular reactivity was assessed with wire myography method. Evaluation of myocardial vascular density: Paraformaldehyde fixed paraffin embedded heart section (40 µm thick) from WT and ESAM KO mice stained with Tomato Lectin (Lycopersicon esculentum) DyLight594 to label vasculature were used. Unbiased automated tracing of the microvasculature was performed using the VesseLucida360 software (MBF), followed by a morphometric analysis (VesseLucida Explorer). Results Transthoracic echocardiography analysis showed that ESAM knockout mice displayed LV diastolic dysfunction, as indicated by a significantly reduced E/A ratio (E=early, A=late mitral inflow peak velocities), increased E/e’ ratio, isovolumic relaxation time (IVRT) and increased E wave deceleration time, with no change in the ejection fraction. The systolic blood pressure was not different between ESAM knockout and WT mice. Heart weight, related to body weight is increased in ESAM-deficient mice, pointing towards cardiac hypertrophy in these animals. Meanwhile, the analysis of the cardiac tissue vascularization with unbiased automated tracing of the microvasculature, reveals the decreased total vascular length per volume of the tissue in ESAM knockout mice. Using wire myography of the pulmonary artery vasodilator function we found that the endothelium-dependent, acetylcholine-induced relaxation of these arteries was significantly reduced in ESAM knockout mice, whereas endothelium-independent, nitric oxide donor, sodium nitroprusside-induced relaxation was similar in the two groups. Conclusion ESAM deficiency in mice resembles a HFpEF phenotype, in that ESAM knockout mice develop endothelial dysfunction and LVDD.